EP2258696A1 - Procédé pour l'obtention de 3-(Benzo[1,3]dioxol-5-yl)-2-methylpropanal enrichi en énantiomères - Google Patents

Procédé pour l'obtention de 3-(Benzo[1,3]dioxol-5-yl)-2-methylpropanal enrichi en énantiomères Download PDF

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Publication number
EP2258696A1
EP2258696A1 EP09425187A EP09425187A EP2258696A1 EP 2258696 A1 EP2258696 A1 EP 2258696A1 EP 09425187 A EP09425187 A EP 09425187A EP 09425187 A EP09425187 A EP 09425187A EP 2258696 A1 EP2258696 A1 EP 2258696A1
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Prior art keywords
ethanamine
group
dioxol
benzo
substituted
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EP09425187A
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German (de)
English (en)
Inventor
Valerio Borzatta
Goffredo Rosini
Paolo Righi
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Endura SpA
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Endura SpA
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Priority to EP09425187A priority Critical patent/EP2258696A1/fr
Publication of EP2258696A1 publication Critical patent/EP2258696A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/54—Radicals substituted by oxygen atoms

Definitions

  • the present invention relates to a process for preparing enriched enantiomers of the compound 3-(benzo[1,3]dioxol-5-yl)-2-methylpropanal (I) of formula:
  • the compound 3-(benzo[1,3]dioxol-5-yl)-2-methylpropanal also known by different trade names such as Tropional® or Helional®, is a commercially important fragrance used in many perfumes. It exhibits a green-floral odour profile (cyclamen) with a fresh, marine, ozone and fresh-cut grass top note ( K. Bauer, D. Garbe, H. Surburg Common Fragrance and Flavor Materials; Wiley-VCH, 1997 ; P. Kraft et al. Angew. Chem. Int. Ed. 2000, 39, 2980 ; E. Brenna, C. Fuganti, S. Serra Tetrahedron: Asymmetry 2003, 14, 1-42 ; M. Shirai et al. (Ube), WO 054997 , 2004 ).
  • the helional molecule exhibits a chiral centre adjacent to the carbonyl group which can easily undergo racemization if strong bases or acids are used or the operating conditions are insufficiently mild.
  • the object of the present invention is therefore to provide the two enantiomers while avoiding the easily triggered racemization during the preparation process.
  • the inventors of the present invention have discovered that by resolving the acid (3) they avoided the drawbacks of the prior art.
  • the resolved enantiomers of the acid (3) can be effectively converted into the respective enantiomers of the alcohol (2) which can themselves be subsequently converted into the enantiomers of Helional® itself, thus avoiding the easily triggered racemization of the prior methods.
  • the invention therefore relates to a process for preparing enriched enantiomers of the compound 3-(benzo[1,3]dioxol-5-yl)-2-methylpropanal (I) of formula comprising the following steps:
  • Ar is preferably a substituent chosen from the group consisting of phenyl, substituted phenyl, benzodioxolyl, substituted benzodioxolyl. If substituted, the aromatic or heteroaromatic ring is preferably substituted with a substituent chosen from the group consisting of methyl, ethyl or methoxy. More preferably, the 1-aryl-1-ethanamine (4) is chosen from the group consisting of 1-phenylethanamine (PEA), 1-(4-methoxyphenyl)ethanamine (MOPEA), 1-(4-methylphenyl)ethanamine (MePEA) and 1-(benzo[d][1,3]dioxol-5-yl)ethanamine (BDEA).
  • PEA 1-phenylethanamine
  • MOPEA 1-(4-methoxyphenyl)ethanamine
  • MePEA 1-(4-methylphenyl)ethanamine
  • BDEA 1-(benzo[d][1,3]d
  • Another aspect of the invention relates to a diastereoisomeric salt of an enantiomer of the phthalic acid monoester (3) and an optically active 1-aryl-1-ethanamine (4) in which Ar is an aromatic or heteroaromatic group having from 6 to 12 members optionally substituted with one or more substituents chosen from the group consisting of (C 1 -C 3 ) alkyl, (C 1 -C 3 ) alkoxy and halogen.
  • One enantiomer of the acid (3) will be mainly present in the diastereoisomeric salt, and the other in the crystallization waters.
  • the enantiomers of the resolved acid in step iii) are converted into the respective alcohols by alkaline hydrolysis. Said alkaline hydrolysis is preferably conducted with KOH in methanol.
  • step iv) the (R) and (S) alcohols are converted into the corresponding (R) and (S) aldehydes, namely the enantiomers of 3-(benzo[1,3]dioxol-5-yl)-2-methylpropanal (1).
  • Said reaction can be conducted by using a NaClO solution preferably at a pH between 8.5 and 9.5 in the presence of potassium bromide and a suitable catalyst such as 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO; P. L. Anelli, F. Montanari, S. Quici. Org. Synth.; Coll. Vol. 8: 367 ) or PIPO ( A. Dijksman, I. W. C. E.
  • racemic phthalic acid monoester ( ⁇ )-3 was then isolated with a 95% yield as a white solid which was sufficiently pure to be used in the resolution step without further purification.
  • a sample was crystallized from ethyl acetate/n-hexane to provide a compound with m.p. of 92-94 °C.
  • Racemic phthalic acid monoester ( ⁇ )-3 was carried out by using enantiomers of a 1-aryl-ethanamine chosen from the following group: 1-phenylethanamine (PEA), 1-(4-methoxyphenyl)ethanamine (MOPEA), 1-(4-methylphenyl)ethanamine (MePEA) and 1-(benzo[d][1,3]dioxol-5-yl)ethanamine (BDEA).
  • PEA 1-phenylethanamine
  • MOPEA 1-(4-methoxyphenyl)ethanamine
  • MePEA 1-(4-methylphenyl)ethanamine
  • BDEA 1-(benzo[d][1,3]dioxol-5-yl)ethanamine
  • the phthalic acid monoester ( ⁇ )-3 (40 g, 117 mmol) was dissolved in a mixture of diisopropyl ether/methanol (4:1 v/v; 450 ml) by heating to reflux under stirring.
  • the (S)-(-)-MOPEA (18.60 g, 116.8 mmol) was then added in portions while maintaining the mixture under agitation.
  • the temperature rose to 65 °C and then the mixture was again heated to reflux to obtain precipitation of a white salt.
  • the mixture was then maintained at reflux under stirring for a further 20-40 minutes.
  • the mixture was then left to cool to ambient temperature while agitating for another 4-8 hours.
  • racemic phthalic acid monoester ( ⁇ )-3 (30.0 g, 87.63 mmol) and (S)-(-)-MePEA (11.85 g, 87.6 mmol) were added to a diisopropyl ether/methanol mixture (9:1 v/v; 330 ml) and the mixture heated to reflux.
  • the suspension thus obtained was cooled to room temperature and maintained under stirring for 8-10 hours.
  • the solid thus formed was filtered off and dried at 25 °C under reduced pressure to obtain 23.50 g of a white solid (PP1).
  • the mother liquors were evaporated under reduced pressure (40 oC/15 mbar) to give 17.61 g of an oil (ML).
  • racemic phthalic acid monoester ( ⁇ )-3 (10.0 g, 29.21 mmol) and diisopropyl ether (100 ml) were heated to reflux under stirring.
  • (S)-(-)-PEA (1.77 g, 14.6 mmol) was added in portions, under stirring and heating was stopped. The mixture was then heated at reflux with formation of an oil.
  • the solution was cooled to room temperature under stirring to obtain a white solid.
  • the solid was then filtered off and dried at 25 oC under reduced pressure to obtain 6.3 g of PP1.
  • the mother liquors were evaporated at reduced pressure (40 oC/15 mbar) to give 5.30 g of an oil (ML).
  • the racemic phthalic acid monoester ( ⁇ )-3 (47.0 g, 137 mmol) was dissolved in a MeOH/water mixture (3:1 v/v; 400 ml), heating to 65 oC under stirring.
  • (R)-(+)-PEA (11.9 g, 96 mmol) was added to this mixture under stirring and heating was stopped. At the end of the addition, the mixture was maintained at 35 oC under stirring after which a solution of NaOH (1.65 g) in water (100 ml) was added. The solution was cooled to room temperature under stirring, then 50 mg of the pure (S)-(+)-PAM • (R)-(+)-PEA salt were added. After a certain amount of time a white solid precipitated.
  • Phthalic acid monoester ( ⁇ )-3 i.e. 2-[(3-(benzo[ d ][I,3]dioxol-5-yl)-2-methylpropoxy]carbonyl)benzoic acid: m.p. 93-94 °C.
  • Phthalic acid monoester ( ⁇ )-3 i.e. (S)-(+)-2-[(3-(benzo[ d ][I,3]dioxol-5-yl)-2-methylpropoxy]carbonyl)benzoic acid : thick oil; [ ⁇ ] D +16.4 (c 0.994, CHCl 3 ).
  • Phthalic acid monoester (-)-3 i.e. (R)-(-)-2-[(3-(benzo[ d ][I,3]dioxol-5-yl)-2-methylpropoxy]carbonyl)benzoic acid: thick oil; [ ⁇ ] D -16.38, (c 0.988, CHCl 3 ).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP09425187A 2009-05-14 2009-05-14 Procédé pour l'obtention de 3-(Benzo[1,3]dioxol-5-yl)-2-methylpropanal enrichi en énantiomères Withdrawn EP2258696A1 (fr)

Priority Applications (1)

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EP09425187A EP2258696A1 (fr) 2009-05-14 2009-05-14 Procédé pour l'obtention de 3-(Benzo[1,3]dioxol-5-yl)-2-methylpropanal enrichi en énantiomères

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Application Number Priority Date Filing Date Title
EP09425187A EP2258696A1 (fr) 2009-05-14 2009-05-14 Procédé pour l'obtention de 3-(Benzo[1,3]dioxol-5-yl)-2-methylpropanal enrichi en énantiomères

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EP2258696A1 true EP2258696A1 (fr) 2010-12-08

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3008968A (en) * 1958-02-11 1961-11-14 Int Flavors & Fragrances Inc Process for making 2-methyl-3-(3'-4'-methylenedioxyphenyl)-propanal
EP0477747A1 (fr) 1990-09-27 1992-04-01 Hoechst Aktiengesellschaft Procédé pour la préparation d'un odorant
CN1365962A (zh) 2001-01-18 2002-08-28 杭州格林香料化学有限公司 胡椒基丙醛的生产工艺
JP2004269376A (ja) 2003-03-06 2004-09-30 Ube Ind Ltd １−ホルミル−３−（３，４−メチレンジオキシフェニル）プロペン誘導体の製法
WO2005004997A1 (fr) 2003-07-04 2005-01-20 Midas Golf Limited Club de golf ameliore
WO2006013399A1 (fr) * 2004-06-23 2006-02-09 EGIS Gyógyszergyár Rt. Intermediaires pharmaceutiques et procede de preparation de ceux-ci

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3008968A (en) * 1958-02-11 1961-11-14 Int Flavors & Fragrances Inc Process for making 2-methyl-3-(3'-4'-methylenedioxyphenyl)-propanal
EP0477747A1 (fr) 1990-09-27 1992-04-01 Hoechst Aktiengesellschaft Procédé pour la préparation d'un odorant
CN1365962A (zh) 2001-01-18 2002-08-28 杭州格林香料化学有限公司 胡椒基丙醛的生产工艺
JP2004269376A (ja) 2003-03-06 2004-09-30 Ube Ind Ltd １−ホルミル−３−（３，４−メチレンジオキシフェニル）プロペン誘導体の製法
WO2005004997A1 (fr) 2003-07-04 2005-01-20 Midas Golf Limited Club de golf ameliore
WO2006013399A1 (fr) * 2004-06-23 2006-02-09 EGIS Gyógyszergyár Rt. Intermediaires pharmaceutiques et procede de preparation de ceux-ci

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
A. C. DA SILVA ET AL., J. MOL. CATAL. A CHEM., vol. 179, 2002, pages 133
A. DIJKSMAN; W. C. E. ARENDS; R. A. SHELDON, CHEM. COMMUN., 2000, pages 271
BOGERT M ET AL., JACS, vol. 53, 1937, pages 2747 - 55
D. ENDERS; M. BACKES, TETRAHEDRON: ASYMMETRY, vol. 15, 2004, pages 1813
E. BRENNA; C. FUGANTI; S. SERRA, TETRAHEDRON: ASYMMETRY, vol. 14, 2003, pages 1 - 42
ENDERS D ET AL: "First asymmetric synthesis of both enantiomers of Tropional<(>R) and their olfactory evaluation", TETRAHEDRON ASYMMETRY, PERGAMON PRESS LTD, OXFORD, GB, vol. 15, no. 11, 7 June 2004 (2004-06-07), pages 1813 - 1817, XP004512332, ISSN: 0957-4166 *
K. BAUER; D. GARBE; H. SURBURG: "Common Fragrance and Flavor Materials", 1997, WILEY-VCH
KISS V ET AL: "Enantioseparation of secondary alcohols by diastereoisomeric salt formation", CHIRALITY, WILEY-LISS, NEW YORK, US, vol. 18, 1 January 2006 (2006-01-01), pages 116 - 120, XP002516880, ISSN: 0899-0042 *
NOHIRA H ET AL: "Optical Resolution by Means of Crystallization", ENANTIOMER SEPARATION,, 1 January 2004 (2004-01-01), pages 165 - 191, XP009123364 *
P. KRAFT ET AL., ANGEW. CHEM. INT. ED., vol. 39, 2000, pages 2980
P. L. ANELLI; F. MONTANARI, S. QUICI. ORG. SYNTH.; COLL., vol. 8, pages 367
W. CHEN ET AL., HANGZHOU GELIN PERFUME CHEMISTRY CO

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